Beneficial Effects of Tanimilast and Formoterol on Mouse Lung Epithelial Progenitors In Vitro

Background: The progressive decline of lung function in chronic obstructive pulmonary disease (COPD) is driven by exacerbations, during which inflammation leads to impaired lung regeneration. Dysfunctional lung epithelial cells contribute to defective repair and tissue remodelling. This study explored regeneration and differentiation mechanisms, focusing on the cAMP pathway, and whether targeting this pathway with the phosphodiesterase 4 (PDE4) inhibitor Tanimilast and the β2 adrenoceptor agonist Formoterol could promote lung repair in vitro. Methods: A mouse lung organoid model and precision-cut lung slices (PCLS) were used to assess the regenerative potential of Tanimilast and Formoterol. In lung organoid studies, injury was induced by cigarette smoke extract (CSE) exposure. In PCLS, injury was induced by treatment with elastase. RNA-sequencing (RNA-seq) was used to identify transcriptional changes. Results: CSE exposure resulted in reduced organoid formation efficiency compared to air-exposed controls. Both combined and single treatments with Tanimilast and Formoterol increased organoid numbers compared to controls, with the most pronounced effect observed in CSE-exposed lung organoids. In PCLS, Tanimilast and Formoterol inhibited negative effects of elastase on alveolar airspace size. Under combined treatment with Tanimilast and Formoterol, RNA-seq analysis revealed positive enrichment of genes involved in epithelial cell differentiation and positive enrichment of genes encoding secreted factors involved in epithelial-mesenchymal signalling in lung fibroblasts, which was strongest in cultures exposed to CSE. Conclusion: Our findings indicate that the combination of Tanimilast and Formoterol, likely through a cAMP mechanism, reverses both the negative effects of CSE on lung organoid formation and the negative effects of elastase on alveolar airspace enlargement in vitro implying beneficial effects in lung regeneration.